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Mutated gene triggers cholesterol drug race

She was a 32-year-old aerobics instructor from a Dallas suburb - healthy, college-educated, with two young children.

She was a 32-year-old aerobics instructor from a Dallas suburb - healthy, college-educated, with two young children. Nothing out of the ordinary, except one thing. Her cholesterol was astoundingly low. Her low-density lipoprotein, or LDL, the form that promotes heart disease, was 14, a level unheard of in healthy adults whose normal level is more than 100.

The reason was a rare gene mutation she had inherited from both her mother and her father. Only one other person, a young, healthy Zimbabwean woman whose LDL cholesterol was 15, has ever been found with the same double dose of the mutation.

The discovery of the mutation and of the two women with their dazzlingly low LDL levels has set off one of the greatest medical chases ever. It is a fevered race among three pharmaceutical companies, Amgen, Pfizer and Sanofi, to test and win approval for a drug that mimics the effects of the mutation, drives LDL levels to new lows and prevents heart attacks. All three companies have drugs in clinical trials and report that their results, so far, are exciting.

"This is our top priority," said Dr Andrew Plump, the head of translational medicine at Sanofi. "Nothing else we are doing has the same public health impact."

Dr Gary Gibbons, the director of the National Heart, Lung, and Blood Institute, estimates that even if the drugs were expensive and injected, as many as 2million Americans might be candidates. But if they could eventually be made affordable and in pill form - two very big ifs - they might be used by one in four adults, he said.

Despite big gains over the past half-century, heart disease affects one in six Australians and remains the leading cause of death in Australia with 45,600 dying in 2011. It is also the leading killer of Americans, causing nearly 600,000 deaths a year. Statins, the cholesterol-lowering drugs that went on the market in 1987, were a huge breakthrough but far from a panacea.

The companies and many heart researchers hope they are closing in on a blockbuster, buoyed by success with preliminary studies. But Gibbons cautioned that critical large-scale studies that would tell whether the drugs prevent heart attacks and deaths are only starting.

"That will show if they are a game changer," he said.

So far, people with stubbornly high cholesterol levels who are taking the drugs in preliminary studies have seen their LDL levels plunging from levels well over 100 to 50, 40 or even lower. Like insulin for diabetes, the drugs are injected, but they are taken once or twice a month.

Dr Barry Gumbiner, who is directing Pfizer's studies, said the company had to decide whether to set a floor for patients' LDL levels. Pfizer is interrupting treatment when LDL levels reach 25 or lower. The people seemed fine, but the company got nervous.

"There is not a lot of experience treating people to LDL levels this low," Gumbiner said.

And there is another concern: cost. Each company's drug is a biologic, a so-called monoclonal antibody made in living cells at an enormous expense, like some new cancer drugs that are already straining the medical system. Amgen plans to make tonnes of its drug, much more, the company says, than any other biologic.

In the US health insurers generally pay for drugs approved by the Food and Drug Administration, and the number who might benefit from these cholesterol drugs dwarfs those who are helped by the biologic cancer drugs.

If the drugs come into use, researchers are asking, can cholesterol go too low?

The data point to increasing benefits with lower and lower LDL levels, said Dr Daniel Rader, a cholesterol researcher at the University of Pennsylvania and a consultant for Sanofi on its drug.

"If I had coronary disease, I would definitely try to drive my LDL to well below 50," Rader said.

But with LDL levels falling so low in studies, Gibbons said, "We are in uncharted territory."

The story of how these drugs came about began a decade ago. French researchers published a short note in the journal Nature Genetics reporting on three generations of a family with astonishingly high LDL levels - up to 466 - and a strong history of heart disease. Cholesterol, a yellow waxy substance that accumulates in clogged arteries, had piled up in their bodies. Some had cholesterol-laden nodules in their tendons that looked like bumps under the skin. The result was heart attacks, strokes and deaths from heart disease at an early age.

The cause of the family's misfortune turned out to be a mutation in a gene called PCSK9, whose function was unknown.

Soon, researchers discovered that the gene slowed the body's ability to rid itself of LDL. In the family studied by the French researchers, the mutated gene no longer worked properly and led to soaring cholesterol levels.

That gave Jonathan Cohen and Dr Helen Hobbs of the University of Texas Southwestern Medical Centre in Dallas an idea. If a mutation in PCSK9 leads to high LDL levels, perhaps there were defects that did the opposite - led to very low levels of LDL and protected against heart disease.

They found what they were looking for in data from a federal study. About 2.5 per cent of blacks in the study had a single mutated PCSK9 gene that no longer functioned. About 3.2 per cent of whites had a less powerful mutation that hampered the gene but did not destroy it.

Since people have two copies of every gene, one inherited from each parent, those with the newly discovered mutations did not have two mutated genes like the aerobics instructor but instead had one fully functioning PCSK9 gene and one that was disabled. Still, the impact was clear. Blacks ended up with LDL levels that were 28 per cent lower than normal, averaging 100 instead of 138. Whites with the less powerful mutation had LDL levels that were about 15 per cent lower.

This led scientists to search for people who had a mutated gene from both parents. Cohen and Hobbs searched their data for a mother and father who both carried a mutation. They found one such couple and tested their daughter in 2006. She was the aerobics instructor with the rare double inheritance. The investigators are still in contact with her and say she remains healthy, but she declined to be interviewed.

Around the same time, South African researchers began their own search for those who have two copies of the gene and found a healthy young woman at a maternity clinic in Zimbabwe. The investigators no longer know her whereabouts.

But those two young women showed that people could be healthy and thrive with very low LDL cholesterol levels.

Then came the hard part: making a drug to create the effects of the mutations. The drug companies were transfixed by the idea, and each wanted to be the first to market it.

The prospect "was so hot it sizzled," said Steven Nissen, the chairman of the department of cardiovascular medicine at the Cleveland Clinic and leader of an Amgen trial.

Amgen has readied three factories, in Colorado, Puerto Rico and Rhode Island, to make its drug. It is anticipating production on a scale never attempted before with a monoclonal antibody, a costly wager for a drug still being tested.

A $70 million, four-storey factory in West Warwick, Rhode Island, is like something out of Brobdingnag in Gulliver's Travels, a land populated by giants. At every stage of production, familiar science equipment has been blown up to a huge scale. Antibody-producing cells that would be housed in a glass flask in a research laboratory are grown in a stainless steel tank nearly the size of a fuel tank on a semi.

The companies want to be ready with large quantities of their versions of the drug if they are approved. "The race is on to see who can do it," said Dr Joseph Miletich, the head of research and development translational sciences at Amgen.

As their factories were starting to produce the drugs, the companies began recruiting patients who were worried enough about their LDL levels to inject themselves with an experimental substance.

Ryan Schmidt, a patient of Rader's, knew since childhood that he had a problem with cholesterol. So did his father, who had his first heart attack at 37 and died of a second at 59.

Schmidt, a brother and two sisters all inherited a genetic condition that caused extremely high cholesterol levels and a high risk of early death from heart disease. So Schmidt, 35, began taking a cholesterol-lowering medication when he was eight. Even after statins came on the market, they did not reduce his LDL enough.

His cardiologist referred him to Rader, who specialises in difficult cases. After failing to significantly reduce Schmidt's LDL levels with three drugs taken simultaneously, Rader suggested the Sanofi trial.

Schmidt and his wife hesitated for months. "It's not an FDA-approved drug," he said. "What if something happened to me?"

He was 17 when his father died and he had to abandon his dream of joining the military and go to work as a carpenter and cabinetmaker to help support his mother.

His father's death "floats in my head", Schmidt said. "I could just have a heart attack at any time."

In March, he joined the study. He does not know if he is getting the drug or a placebo. But once his part in the trial ends, he will be able to take the drug, if he wants it, until the FDA decides whether to approve it.

In the meantime, his genetic inheritance continues to shape his life. He and his wife would like to have children, but they plan to take in foster children or to adopt.

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